New 16-substituted pregnenes



United States Patent Office 3,195,149 Patented July 20, 1965 3,196,149, NEW Io-SUBSHTUTED PREGNENES Martin 5. Weiss, Oradeil, N.J., Henry M. Kissmnn,

Nannet, N.Y., and Ariene M. Hoiiman, Park Ridge,

N31, assignors to American Cyanamid Company, New

York, N.Y., a corporation of Maine No Drawing. Filed Mar. 6, 1%2, Ser. No. 177,748

24 Claims. (61. 2s0 2s9.s

This invention relates to new steroid compounds. More particularly, it relates to lo-substituted steroids of the pregnane series and methods of preparing the same.

The novel steroids of this invention may be represented by the following structural formula.

radicals; R is a member of the group consisting of hydrogen, hydroxyl and lower allcanoyloxy radicals; R is a member of the group consisting of sulfhydryl, lower alkanoylthio, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyanothio, chlorine, a-nitro substituted lower alkyl, mono-lower alkylamino, dilower alkylamino, mononuciear arylamino, cyclopentamethylenimino and lower alkoxy radicals and when R is a member of the group consisting of chlorine, wDlIIO substituted lower alkyl, lower alkylthio, cyanothio and lower alkoxy, then at 5, is a member of the group consisting of C and :0 11" --r radicals and when R is a member of the group consisting of sulfhydryl and lower alkanoylthio then R is a member of the group consisting of hydroxyl and lower alkanoyloxy radicals.

The compounds of this invention are prepared by adding reagents such as lower alkanoylthiols, lower alkylthiols, metal isothiocyanates, hydrogen chloride, alcohols, nitroalkanes and lower alkyl amines to appropriate 16- dehydro-ZO-keto steroids such as, for example, 16-dahydroprogesterone, 16-dehydrodeoxy-corticosterone and its 2l-acylates, 9a-fiuoro-2l-hydroxypregna-4,16-diene- 3,11,20-trione and its 21-acylates and 9a-fiuoro-11fi,2ldihydroxypregna4,16-diene-3,ZO-dione and its acylates. Depending upon the reagents used the reaction is carried out under conditions of acid or base catalysis.

When sulfur reagents are reacted with 16-dehydro-20- keto steroids starting materials the reaction usually is carried out in a solvent such as acetic acid, containing a strong acid, such as hydrochloric acid and at a relatively low temperature, usually within the 5 to C. range, for an extended period of time which may be from 2 to 6 days. In some instances, such as with isopropylthiol, concomitant addition at the C position and conversion of the A -3-ketone to a thioenol ether may take place. The thioenol ether, if desired, may be preferentially hydrolyzed to the A -3-keto compound with dilute acid. The l6sulfhydryl derivatives may be obtained from the lo-alkanoylthio derivatives by treatment with dilute methanolic sodium methoxide. The alkylsulfinyl derivatives are obtainable by oxidation of the alkylthio derivatives with an equivalent of a per acid, such as monoperphthalic acid. Further oxidation of the alkylsulfinyl derivative with a second equivalent of the per acid will produce the corresponding alkylsulfonyl steroid derivatives of the present invent-ion.

The lo-chloro steroids of the invention are prepared by treating a 16-dehydro-20-keto steroid of the pregnane series with a solution of anhydrous hydrogen chloride in an inert solvent such as, for example dioxane, chloroform or the like, at relatively low temperatures, such as -10 to +10 C., for from two to six days.

The 16-nitroalkyl derivatives are prepared by treating a 16-dehydro-20l eto steriod of the pregnane series with a nitroalkane, which reagent may also serve as the solvent, in the presence of a base such as a tertiary amine, for example-triethylamine or the like. The reaction is usually carried out at temperatures in the range of 20 to 60 C. for from two to six days. In the case of the nitroalkane additions, it is usually desirable to block the 3-keto position of the steroid with an alkali-stable, acidlabile group. A 3-ethylenedioxy group has been found useful for this purpose. The 3-keto group of the steroid may be regenerated readily in a subsequent step by mild acid treatment.

The 16-amino derivatives are obtained by treating a 16-dehydro-20-keto steroid of the pregnane series with a primary or secondary amine in an inert solvent, such as tetrahydrofuran, in the presence of an alkaline catalyst, such as an ion exchange (OH) resin, at a temperature in the range of 10 to C. for a period of from 8 hours to 6 days.

The products of this invention are usually White, crystalline solids and are isolated and purified by the usual techniques of washing, evaporation, recrystallization and chromatography.

The substituents in the C position and the 17-hydrogen in the steroids of this invention are assigned the ac-configuration. This configuration has been designated in order to provide a more complete exposition of the present invention and in order that the specification shall constitute a more useful contribution to the art and is based upon the present conception of organic theory, in particular the Rule of the Rear and an interpretation of molecular rotation data. Therefore, this designation is not to be interpreted except in relation to the state of the art presently understood by organic chemists. It will be apparent that no part of the specification will be materially defective if it should later be established that the configuration is the opposite of that deducible from data presently available to workers in the field.

The steroids of this invention inhibit the growth of microorganisms. When tested by standard agar dilution techniques the compounds for example, inhibit the growth of fungi such as Chaefomium globosum, Trichophyton mentagrophytes, Microsporum. gypseum and Penicillium digitatum and of bacteria such as Staphylococcus aureus, Bacillus subrilis, Eschericia coli and Salmonella gallz'namm. The compounds of this invention having an oxygen function at position 11 of the steroid nucleus have adrenocorticoid and anti-inflammatory activity and are useful in the treatment of arthritis, various inflammatory diseases and dermatological disorders. The ll-oxygenated steroids in some instances are not salt retainers although the parent 16-unsubstituted derivative is a very potent salt retainer.

The compounds of this invention which are 16-substituted progesterone derivatives have progestat-ional activity and are useful in progestational replacement therapy such as in the treatment of habitual abortion, being administered in the same type of parenteral preparations as progesterone with the activity of the particular compound determining the dosage.

The following examples illustrate in greater detail the preparation of representative steroids of the present invention.

PREPARATION 1 Qa-fluora-Z1-hydr0xy-4,I6-pregnqdien-3,1 1,20 trione A mixture of 9a-fluoro-17a,21-dihydroxy-4-pregnene- 3,11,20-trione (9a-fluorocortisone) [1. Fried and E. F. Sabo, I. Am. Chem. Soc., 79, 1130 (1957)] (5.6 g.) and ethylene glycol (125 ml.) is concentrated to a volume of 100ml. under vacuum (2 mm.) at a stillhead temperature of- 100 C. Para-toluenesulfonicacid monohydrate (225 mg.) is added and slow distillation continued with vigorous stirring for a period of 2%. hours. The mixture is neutralized with aqueous potassium hydroxide solution (3 ml., 10%) and water is added. chloroform is added and the layers are separated. The aqueous layer is extracted with chloroform and the chlorofiorm extracts are combined. The organic extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. This gives a glassy residue which, when slurried with acetone, yields crystalline 9wfluorocortisone 3,20-bisethylene-ketal (3,20-bisethylenediox -9a-fluoro-17a,21-di-hydroxy-S-pfegnen-ll-one) (1.38 g., melting point 241-244" C.) Concentration of the mother liquor yields an additional 0.51 g., melting point 242-245 C. (total yield 27%). Both fractions give negative a-ketol tests with bluetetrazolium. Recrystallization of the main portion raises the melting'point to 251- -253 --34' (c., 1.1 in. CHCl 2332 none at; a concentration of 20 ml.,

25?; 3570, 1722, 1680, 1094 and 1054cmf A- solution of 3,20-bisethylenedioxy-9a-fiuoro-1712,21- dihydroxy-S-pregnen-l1=one (2.17 g.) in pyridine (35 ml.) is treated with acetic anhydride (10 ml.) and allowed to stand 50 hours at roomtemperature. The mixture is poured into ice water and the crystalline 9a-fluorocortisone 3,20-bisethylene ketal 21 acetate (21-acetoxy-3,20- bisethylenedioxy 90 fluoro-17oc-hydroxy-5-pregnen-l-1- one) is collected by filtration 223 g. (9 melting point, 2-10-215" C. (dec.). Recrystallization from acetoneraises the melting point to 227 C. (dec.); [a];, .26;

1 2?; 3522, 1748, 1726, 1234. and 1050 cm.-

A solution of 2l-acet-oxy-3,20-bisethylenedioxy-9u-fiuoro-lla-hydroxy-S-pregnen-ll-one (2.03 g.) in pyridine (.85 ml.) is chilled to; 5 'C. and'thionylchloride (8 ml.) is. added. The mixture-is allowed to stand overnight at 5 C., and then poured into ice water. The oily mixture isextractedwith ethyl acetate, the extract is washed with saturated saline, dried and evaporated. The residue is triturated with'methanol and'the crystalline 21-acetoxy- 3,20-bisethylenedioxy-9wfluoroJ,16-pregnadien-1 l-one is collected by, filtration to give 0.68 g., melting point 110- 113 C. An additional 0.1 g., melting point 110 C., is obtained by concentration of the mother liquor (combinedyield, 37%). Recrystallization of the combined xggg 237 my (6 25,800), r

fractions from methanol raises the melting point to 126- 129 0., 67 32;

112,, 1733, 1616, 1240 and 1042 cmf A solution of 9a-fluoro-2l-acetoxy-3,20-bisethylenediox-5,l6-pregnadien-11 one (20.0 g., 0.045 mole) in 500 ml. of methanol containing 25 ml. 8% sulfuric acid (v./v.) is stirred at reflux for one hour. The cooled' reaction mixture is neutralized with 10% sodium hydroxide solution and the solvent is evaporated until all the meth anol is removed. The residual aqueous suspension is poured into ice water and this mixture is extracted with methylene chloride. The combined organic extracts are washed with water and saline solution, dried, decolorized and evaporated. The residue is crystallized from methylene chloride-ether to yield 11.3 g. (69%), melting point 210-230 C. Three recrystallizations from methylene chloride-ether and once from acetone gives material with melting point 225-235 C., +172 (1.6% in chloroform);

CHQOH 236 m, (625,200); my; 2.95, 5.79, 5.96, 6.13,

max

PREPARATION 2 21 -acet0xy-9a-fluoro-4,1 6 -p7'egnadiene-3 ,1 1,20-tri0ne To a chilled solution of 9a-tluoro-21-hydroxy-4,l6- pregnadiene-3,l1,20-trione (Preparation 1) (6.0 g., 16.6 moles), and pyridine (40 ml.) is added acetic anhydride (10 ml.). The mixture is stirred at room temperature. After 18 hours the mixture is added slowly with stirring to ice water (750 ml.). The resulting precipitate is collected by filtration, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with water and saline solution, dried, decolorized and evaporated. The residue is crystallized from methylene chloride-ether to give 5.67 g. (84%), melting point 208-216 C. The product is then recrystallized three times frommethylene chloride-ether togivematerial with melting point 217220 C., [aJ +=175 (0.99% in chloroform) max.

General procedure A A solution or" a A -2O-keto steroid (500 mg.) in glacial acetic acid (25 ml.) is chilled and concentrated hydrochloric acid (1.0 ml.) is added. To this solution is added a three to ten-fold excess of the appropriate sulfur nucleophile (methyl merc-aptan, ethyl mercaptan, isopropyl mercaptan, potassium thioacetate, potassium thiocyanate). When the potassium thioacetate or potassium thiocyanate is used, the amount of hydrochloric acid is increased by an equivalent quantity. The reaction vessel is stoppered, and stored at 57 C. for 4 days. The solvent is then evaporated at, less than 30 C. The residue is partitioned between methylene chloride and water. The organic phase is washed with saturated sodium bicarbonate solution, water and saline solution, dried, decolorized and. evaporated. The residual material is crystallized from ether, methylene chloride-ether or hexane. The compounds are then further recrystallized frommethylene chloride-ether. The yields, physical properties. and analytical data for the various products are listed in Table I. (Examples 1-7.)

Condensation of isopropyl mercaptan with 21-acetoxy- 9a-fluoro-4,l6-pregnadiene-3,l1,20-trione by the above procedure gives a 31% yield of 21-acetoxy-9a-ftuoro-3, 16 bisisopropylthio-3,S pregnadiene-l1,20-dione, melting point 105-109 C., [(21 8.6 (1.14% in chloroform);

rig; 5.70

The hydrolysis of this product to the l6ct-isopropylthio- A -3-ketone is described below.

General procedure B The methylthio compound is dissolved or suspended perature in a nitrogen atmosphere (no nitrogen is used with me-thylamine) for l to 4 days. With 16-dehydrodeoxycorticosterone and pipcridine a 24 hour reaction period gives superior results to those obtained with more prolonged reaction periods. With 21-acetoxy-9a-fluoro- 4,16-pregnadiene-3,11,20-trione, the reaction periods are usually from two to four days. The mixture is then filtered and the resin is washed with tetrahydrofuran. The combined filtrate and washings are evaporated (at less than C.) and the residue is partitioned between methylene chloride and water. The organic phase is Washed with water and saline solution, dried, decolorized and evaporated. The residual material i crystallized with ether or methylene chloride-ether to yield the desired le-substituted amino derivatives. These compounds are described in Table 1. (Examples 14-19.)

TAB LE I.-EXAMPLES 21-19 Melting [0111), Example Compound prepared Yield, Point, degrees A CHROH Steroid 1 Start- Reagent Procedure Percent (in chloromam, mu(e) ing Material Used form) 1 9a-fluoro-16u-methylth1o-11-dehydro- 77 182-184 +142 234 (18,000) (A) Mctl 1ylmcrcaptan A.

corticosterone acetate. 2 IGIx-methylthioprogesterone 58 146-150 +118 240 (14,400) (B) do A. 3 lfia-inethylthiodeoxy-corticosterone 31 159-162 +11 241 (19, 600) (C) .do A.

ace a e. 4 16a-ethylthio-tla-fluoro-ll-dehydro 30 118-120 +137 235 (17,150) (A) Ethylmercaptam. A.

corticosterone acetate. 5 lfia-acet-ylthi0-9a-fiuoro-1Ldehydro- 67 159-163 +64 235 (23,600) (A) Thioacctic acid... A.

corticosterone acetate. 6 Ida-agelylthiodeoxycorticosterone 23 153-155 +71 238 (20,100) (0) do A.

ace a e. 7. 16u-cyan0thio-9a-fiuoro-11-dehydro- 32 199-202 +77 245 (17,800) Thiocyanic acid-" A.

corticostcrone acetate. 8 9:141uorodea-methylsulfinyl-ll-de- 64 171-174 +248 230 (17,200) Product of Mono pcrphthalic B. hydrocorticostcrone acetate. Example 1. acid. 9 lfia-methylsulfinylprogesterone 164-168 +198 240 (16,200) Pggduct (121 .do B.

xampc2. 10 lfia-metnylsulfinyl deoxycorticos- 84 149-154 Product of do B.

terone acetate. Exmple 3. 11 9u-fiuor0-16u-methylsulfonyl-ll-de- 82 208-211 +160 23-1 (10,100) Product of do C.

hydrocorticosterone acetate. Example 8. lfia-methylsulfonylprogesterone 79 229-232 239 (17,400) Product of do C.

Example 9. 1fia-methylsulionyldeoxy-corticos- 65 174-178 +116 240 (17,500) Product or do C.

terone acetate. Example 10. 14 9a-fiu0ro46mmethy1amin0-1l-dehy- 48 152-158 +132 235 (18,100) (D) Mcthylamine D.

drocorticosterone, (dec) 15 Qa-fiuorodfia-piperidiho-l1-dehydr0- 31 171-174 234 (17,000) (D) Piperidine D.

corticcsterone. 16 9a-fiuoro-16a-dimethylamino-11-dc- 13 -162 (D) Dimethylamine D.

hydrocorticosterone. 17 1Got-aniline-9a-fluoro-11-dchydr0corti- 63 180-183 (D) Aniline D.

costerone. 18 1fia-piperidinodeoxy-corticosterone 36 160-169 +78 240 (18,200) (E) Piperdine D. 19. lfia-metliylaminodeosy-corticosterone1 145-160 (E) Mcthylamine D,

l (A)=21-acetoxy-9a-iluoro-4,16-pregnadiene-3,11,20-tri0ne.

(B )=16dehydroprogesterone. (C)=16-dehydrodeosycorticostcrone acetate. (D)=9a-fluoro-21-hydroxy-4,lfi-pregnadiene-3,11,20-tri0ne. (E)=1fi-dehydrodeox vcorticosterone. acetone or petroleum-ether (boiling point 60-70" C.) EXAMPLE 2O acetone and collected by filtration. The product may be recrystallized from acetone or acetone-petroleum ether. The compounds obtained by this general procedure are shown in Table 1. (Examples 8-10.)

General procedure C General procedure D A four to ten-fold excess of the requisite amine (Table I) is added to a solution of a A -20-keto steroid (1 mole) dissolved in tetrahydrofuran (5.0 ml.). With methylamine, the steroid solution is saturated with the gaseous amine. With aniline, dioxane is used as the solvent. To the solution of steroid and amine is added ion exchange resin (OH) and the suspension is stirred at room tem- A suspension of 21-acetoxy-9u-iluoro-3,16-bisisopropylthio 3,5 pregnadien 11,20 dione (250 mg, 0.47 mmole) in ethanol (30 ml.) containing water (2 ml.) and 6 N hydrochloric acid solution (0.2 m1.) is refluxed for 2 hours. The reaction mixture is poured into ice Water and extracted with ether. The combined ether extracts are Washed with sodium bicarbonate solution, water and saline solution, dried, decolorized and evaporated. The residue is crystallized from ether to yield 100 mg. (45%). melting point -180 C. Further recrystallization from ether give material with melting point ISO-184 C., [041 +112 (chloroform);

EXAMPLE 21 Preparation of 16ot-acetylthio-Qa-fluoro-ZJ-hydr0xy-4- pregame-3,11,20-trione A solution of 21-acetoxy-16c-acetylthio-9a- .uoro-4- pregnene-3,11,20-trione 410 mg, 0.86 mmole) in methanol (49 ml.) containing perchloric acid (72%, 1.25 ml.)

is magnetically stirred at room temperature for hours. The mixture is neutralized with 10% potassium acetate solution and the resulting precipitate is removed by filtration and washed with methanol. The filtrate and methanol washings are combined and partially concentrated and the residue is partitioned between methylene chloride and water. The organic phase is washed with water, 10% potassium acetate solution, water, and saline solution, dried, decolorized and evaporated to leave 379 mg. of a white glass. The glass (326 mg.) is dissolved in ml. of the lower phase of the solvent system: heptane-ethyl-acetate-methanol-water (80:20:12z8), and grams of diatomaceous earth is added to the solution. The mixture is placed on top of a chromatographic column prepared from 100 g. of diatomaceous earth which had been mixed thoroughly with 50 ml. of the lower phase of the above described solvent system. The column (hold-back volume=l28 ml., hold-back volume is defined as the volume of solvent necessary to fill the packed column) is eluted with the upper phase of the abovedescribed solvent system and the efiluent is allowed to pass through a recording spectrophotometer (set at 240 mu). There are obtained two major peaks of material with absorption at this wave length. The first peak occurs at the second and third hold-back volumes and the crystalline material (60 mg.) isolated from this fraction has the same infrared absorption spectrum as that of the starting material. The second peak occurs at the 7th through 11th hold-back volumes and contains 192 mg. (51%) of white crystalline material, melting point 136- 143 C. This product is recrystallized three times from acetone-hexane to give 16a-acetylthio-9a-fluoro-2l-hydroxy-4-pregnene-3,l1,20-trione with melting point 148- 154 C.

EXAMPLE 22 Prepanation of 9a-flu0r0-21 -hydr0xy-1 6 a-mercap t0-4- magnate-3,1 1,20-tri0rte A solution of 21-acetoxy-16a-acetylthio-9or-fiuoro-4- pregnene-3,l1,20-trione (239 mg., 0.5 mmole) in 0.9 N methanolic sodium methoxide is magnetically stirred at room temperature for minutes. The mixture is neutralized with acetic acid and evaporated. The residue is partitioned between methylene chloride and water, and the methylene chloride solution is washed with water and saline solution, dried, decolorized and evaporated to leave 180 mg. of colorless gum. Crystalline material (23 mg., 12%) with melting point 2502'52 C. is obtained by crystallization from methylene chloride-ether. This product is 16,16 thio-bis-(9ct-fluoro-21-hydroxy-4-pregnene- 3,11,20-trione). From the methylene chloride-ether mother liquors there is obtained 75 mg. (38%) yield of a second crystalline product (melting point 178-193 C.). This substance is recrystallized from methylene chloride-ether to give 9ct-rluoro-2l-hydroxy-lGa-mercap- 'to-4-pregnene-3,l1,20-trione melting at 183-488 C.,

[(11 +162 (chloroform);

EXAMPLE 23 Preparation of 21-acet0xy-16a-chl0r0-9a-flu0r0-4- pregnene-3J 1 ,ZO-trione A chilled dioxane solution (25 ml.) of 21-acetoxy-9afluoro 4,16 pregnadiene-3,l1,20-trione (402.5 mg, 1 mmole) is saturated with hydrogen chloride. The reaction vessel is stoppered and stored at 57 C. for 4 days. The acid solution is neutralized by cautiously passing it into a chilled mixture of aqueous saturated sodium bicarbonate solution and methylene chloride. The aqueous layer is extracted with methylene chloride and the combined methylene chloride extracts are washed with water, saline solution, dried, decolorized and evaporated. The residue is trlturated with ether to give a white solid (67%), melting point 9598 C. Repeated recrystallization from methylene chloride-ether gives material melting at 96 C., solidifying and remelting at 176179 0., [M +163 (chloroform);

max.

EXAIJPLE 24 A solution containing 640 mg. (1.59 mmoles) of 21- acetoXy-9ut-more-4,l6-pregnadiene-3,11,20-trione and 15 mg. of p-toluenesulfonic acid in 14 ml. of 2-ethyl-2 methyl-1,3-dioxolane is refluxed with partial distillation through a helices-packed column for 5 hours. Approximately 6 ml. of distillate is collected during this period. The cooled solution is diluted with 30 ml. of benzene and is washed with sodium bicarbonate solution and then with water. The organic phase is dried over sodium sulfate and is evaporated to give a residue, 21-acetoxy-3- ethylenedioxy 90c fluoro-5,16-pregnadiene-11,20-dione, which is crystallized in ether, 530 mg., melting point 165 169 C. This material may be recrystallized several times from ether-methylene chloride to give 431 mg. (60%) with melting point 195196 C.,

(0.8% in chloroform);

A solution of 21-acetoxy 3 ethylenedioxy-9ot-fluoro- 5,16-pregnadiene-11,20-dione (223 mg, 0.5 mmole) in nitromethaue (2.26 ml.) containing 0.61 ml. of triethylamine is allowed to stand at room temperature for 4 days. The solvent is then evaporated (at less than 30 C.) to leave a crystalline residue which is triturated with ether to yield 190 mg. (75%) of 21acetoxy-3-ethy1enedioxy-9a-fluoro-16et-nitromethyl-S-pregnene-11,20 dione with melting point 188-198 C. Three recrystallizations from methylene-chloride-ether gives material with melting point 188205 C.

A suspension of 21-acetoxy-3-ethylenedioxy-9a-fluoro- 16a-nitr0rnethyl 5 pregnene-l1,20-dione (250 mg., 0.5 mmole) in 6 ml. of methanol containing 0.6 ml. of 8% (v./v.) aqueous sulfuric acid solution is magnetically stirred and refluxed for 2 hours. The white solid is collected by filtration, washed with methanol and dried under reduced pressure over phosphorous pentoxide to yield 154 mg. (67%) of 21-acetoxy-9ot-fiuoro-16a-nitr0- methyl-4-pregnene-3,11,20-trione with melting point 234- 237 C. Three recrystallizations from methylene chlo ride-ether gives material with melting point 239242 C.;

[@ +188 (chloroform);

EXAMPLE 25 Preparation 0 f 9a-flu0r0-21-hydr0xy-1 6 a-methoxy- 4 -pregnene-3 ,1 1,20-tri0ne 21-acetoxy-9u-fiuoro 4,16 pregnadiene-3,11,20-trione (6.0 g.) is dissolved in reagent methanol (500 ml.) and to this solution is added an 0.1 N methanolic sodium methoxide solution (23.5 ml.). After 30 minutes standing at room temperature in a nitrogen atmosphere, the solution is neutralized with acetic acid. Evaporation of solvent under reduced pressure gives a semi-solid which is partitioned between water and methylene chloride The methylene chloride extract is washed with saturated sodium bicarbonate solution and then with water. After drying over sodium sulfate, the solvent is removed and the residual material is recrystallized from methylene chloride-ether to give 3.2 g. of 9o -fiuoro-21-hydroxy-4,16- pregnadiene-3,11,20-trione, melting point 199 C., recrystallization from the same solvent pair gives 1.6 g. with melting point 215222 C.

CHaOH max.

We claim: I. A steroid of the formula:

CHPORI wherein C is selected from the group consisting of wherein R and R represent lower alkanoyl.

3. A steroid of the formula:

1G 4. A steroid of the formula:

5. The 16a-1OW6I alkylthio-9a-fluoro-1l-dehydrocorticosterone-Zl-lower alkanoates.

6. The 160: lower alkylthiodeoxycorticosterone 21- lower alkanoates.

7. The 16oc-1OW61 alkanoylthio-9ot-fiuoro ll dehydrocorticosterone-Zl-lower alkanoates.

8. The 16cc-1OWe1 alkanoylthiodeoxycorticosterone-21- lower alkanoates.

Q The compound 9a-fiuoro-21-hydroxy-16u-mercapto- 4-pregnene-3 ,1 1,20-trione.

10. The IGu-(a-nitro lower alkyl)-9a-fluoro-11-dehydrocorticosterone-Zl-lower alkanoates.

11. The 9u-flUOIO-2I-hYdIOXY-16u-1OW61' alkoxy-4-pregmeme-3,1 1 ,ZO-triones.

12. The compound 9a-fluoro-16a-methylthio-1l-dehydrocorticosterone acetate.

13. The compound 16a-acetylthio-9a-fiuoro-1l-dehydrocorticosterone acetate.

14. The compound 160a methylsulfinyldeoxycorticosterone acetate.

15. The compound 9a-fluoro-l6a-methylamino-1l-dehydrocorticosterone.

16. The com ound 16a-piperidinodcoxycorticosterone.

17. The compound 16cc methylaminodeoxycorticosterone.

18. The compound 21-acetoxy-9a-fiuoro-16a-isopropylthio-4-pregnene3,11,20-trione.

19. The compound 2l-acetoxy-16a-chloro-9u-fiuoro-4- pregnene-3,11,20-trione.

20. The compound 21-acetoXy fluoro-16a-nitromethy1-4-pregnene-3,l 1,20-trione.

21. The compound 9a-fluoro-21-hydroxy-16a-methoxy- 4-pregnene-3, 11,20-trioue.

22. The compound 90: fluoro-16a-methyl-su1fonyl-11- dehydrocorticosterone acetate.

23. The 21-lower alkanoyloxy 3 ethylene-dioXy-9ufluoro-16a-(a-nitro lower alkyD-S-pregnene-l1,20-diones.

24. The compound 2l-acetoxy 3 ethylene-dioxy-9afluoro-l6a-nitromethyl-S-pregnene-1 1,20-dione.

References Cited by the Examiner UNITED STATES PATENTS 2,912,443 11/59 Dodson et a1. 260-3973 2,988,557 6/61 Reimann et a1 260397.45

LEWIS GOTTS, Primary Examiner. MORRIS LIEBMAN, IRVING MARCUS, Examiners. 

1. A STEROID OF THE FORMULA 